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Fatty Acid Synthesis


Summary of Fatty Acid Synthesis Reactions:

Each cycle through the malonyl-CoA pathway results in two carbons being added to the FA chain.

The total reaction is (given here for synthesis of palmitate; C16):

Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH2 are catalyzed by Fatty Acid Synthetase to yield =

Palmitate + 7 CO2 + 14 NADP + 8 CoA

The Fatty Acid Synthesis Pathway involves the following steps :

Activation - acetyl-CoA carboxylation

Elongation - the malonyl-CoA pathway

condensation step
reduction step
dehydration step
another reduction step

The cycle is then repeated.

The steps involved in the malonyl-CoA pathway occur with the growing FA chain esterified to an acyl carrier protein.

Fatty acid synthetase is a large complex of enzymatic activities which are responsible for the reactions of FA synthesis. In addition, there are enzyme activities called acylthioesterases which are responsible for cleaving off the growing FA chain from the acyl carrier protein once it has reached a certain chain length. The long chain acylthioesterase is part of the fatty acid synthetase complex and cleaves off FA chain lengths longer that C16. The medium chain acylthioesterase cleaves off the growing FA chain at or before it reaches C16. In nonruminants, the medium chain acylthioesterase is cytoplasmic and cleaves off free FAs (unesterified). In the ruminant, the medium chain acylthioesterase is associated with the fatty acid synthetase complex and releases acyl-CoA thioesters.

Below is a diagram of the pathway of fatty acid synthesis. Note that acetate carbons come into play twice, once as the source of acetyl-CoA to enter the malonyl-CoA pathway and once as the source of malonyl-CoA that adds the two carbons to each cycle of the fatty acid synthetase. In the latter case, conversion of acetyl-CoA to malonyl-CoA is the rate limiting step in fatty acid synthesis. The reaction is catalyzed by acetyl-CoA carboxylase, a biotinylated protein. Acetyl-CoA carboxylase activity is regulated by lactogenic hormones and is one of he enzymes up-regulated during the first stage of lactogenesis. In the Malonyl-CoA Pathway, the condensation step is the covalent linking of acetyl-CoA and Malonyl-CoA (with the release of CoA and carbon dioxide), the first reduction step is the conversion of acetoacetyl-ACP to ß-hydroxybutryl-ACP (using up one NADPH2), the dehydration step is the conversion of ß-hydroxybutryl-ACP to crotonyl-ACP (with the release of a water molecule), the second reduction step is the conversion of crotonyl-ACP to butryl-ACP (using up a second NADPH2). Butryl-ACP would then condense with another malonyl-CoA to start the second cycle. Even though malonyl-CoA is a three carbon primer, one carbon is lost in the condensation step and therefore only two carbons are added to the growing fatty acid chain at each round.


ß-Hydroxybutyrate (BHBA) : Can enter the cycle as a primer only. It cannot be used in FA synthesis at later stages. It contributes up to 50% of the first 4 carbons. BHBA cannot be split into acetate in the cytosol, but can be converted to 2 acetyl-CoA's in the mitochondria. However, these acetyl-CoA's cannot leave the mitochondria, and are therefore not available for FA synthesis.

FATTY ACID SYNTHESIS in Summary:

  • it occurs in the cytoplasm
  • the intermediates are linked to ACP (acyl carrier protein)
  • the enzymes of FA synthesis are linked in a complex
  • elongation occurs by 2 Carbons/cycle (source of 2-Carbon units is always acetyl-CoA at the beginning of each cycle)
  • the required reducing agent is NADPH2
  • in general, elongation stops at C16

These two things are required for de novo Fatty Acid synthesis:

  • a source of carbons, specifically acetyl-CoA
  • a source of reducing equivalents, specifically NADPH2

The origin of each of these varies among species, particularly in comparing ruminants and nonruminants.


Ruminant vs. Nonruminant Fatty Acid Synthesis

Several distinct differences exist between ruminant and nonruminant species with regard to the mechanisms of fatty acid synthesis. These differences are relevant to the type of fatty acids which are found in the milk of various species, the role of glucose in fatty acid synthesis in various species, and the effect of dietary lipids on milk fat fatty acid composition in various species. For example, in ruminants dietary and carbohydrates fats are generally metabolized in the rumen so that the primary source of carbons for FA synthesis by the mammary gland are acetate and BHBA. Glucose is limiting in ruminants. In addition, the absence of citrate lyase in ruminants means that little glucose carbons end up being used for FA synthesis. Nevertheless, glucose is required for generation of reducing equivalents in ruminants and nonruminants.

Several differences also exist between species in the specific enzyme activities associated with NADPH2 generation. NADPH2 supplies the necessary reducing equivalents for the Fatty Acid Synthesis Pathway.

Acetyl-CoA carboxylase is a key milk fat synthesis enzyme activity which increases during lactogenesis. There is a close relationship between observed fatty acid synthesis by the mammary tissue and the activity of acetyl-CoA carboxylase during lactogenesis and lactation.


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